Clue to Cystic Fibrosis Lung Infection

One mystery of cystic fibrosis is why most children suffer chronic and often deadly lung infections from a bug that rarely harms healthy individuals. Now researchers have found that immune cells in patients with cystic fibrosis react differently to the bug, Pseudomonas aeruginosa, provoking a vicious inflammatory response.

Roughly 30,000 people in the United States suffer from cystic fibrosis, and despite research advances, many still die in early adulthood--nearly all of chronic lung inflammation prompted by P. aeruginosa. Previously, Sam Miller, a microbiologist at the University of Washington, Seattle, and his colleagues had determined that the bacteria change a component of their surface, called lipopolysaccharide (LPS), in the airways of patients with cystic fibrosis by adding an extra fatty acid. Miller wondered whether this structural variation could help explain why the bug can be so devastating.

To find out, his team turned to a collection of P. aeruginosa bacteria that doctors at Children's Hospital in Seattle began collecting several years ago from the respiratory tracts of their patients with cystic fibrosis. Miller's group exposed the LPS from the bugs to the immune system receptors called TLR4-MD-2, which are known to recognize LPS and trigger an immune response. In the 25 March online edition of Nature Immunology, they report that it took between 50 and several hundred times less bacteria from the samples than controls to send TLR4-MD-2 receptors into overdrive. That hyper-response, Miller theorizes, is not unlike what's seen in autoimmune diseases, where the inflammation provoked by an immune system attack proves far more damaging than any pathogen itself.

Miller's team then conducted the same experiment in mice, comparing whether the mouse version of TLR4-MD-2 reacted differently to the two distinct versions of P. aeruginosa. In mice, the receptor didn't seem to care one way or the other: The same amount of bacteria provoked the same response whether the samples had an extra fatty acid or not.

"This CF mouse doesn't get chronic Pseudomonas the way patients do," says Doug Golenbock, chief of the division of infectious disease and immunology at the University of Massachusetts Medical School in Worcester. That, he says, suggests that the widely used mouse model of cystic fibrosis "might not be appropriate."